Cephalosporin antibiotics have recently achieved considerable success in the treatment of infectious diseases of man. This particular class of antibiotics has been prepared by two known general procedures. In the first of these methods, cephalosporin C is produced by culturing the organism Cephalosporium acremonium, Newton and Abraham, Biochem. J., 62, 651 (1956). Cleavage of the cephalosporin C 2-aminoadipoyl side chain according to the method described in U.S. Pat. No. 3,188,311 affords 7-aminocephalosporanic acid (7-ACA). Acylation of 7-ACA with an appropriate acid halide or mixed anhydride yields the expected 7-acylaminocephaloporanic acid. The cephalosporin antibiotics obtained from cephalosporin C according to this method are derivatives of cephalosporanic acid which are substituted at the 3-position of the cephalosporin nucleus with an acetoxymethyl group. According to the cephem nomenclature system for cephalosporins, the cephalosporin antibiotics obtained from cephalosporin C are named 7-acylamido-3-acetoxymethyl-3-cephem-4-carboxylic acids.
The second method by which the cephalosporin antibiotics are prepared involves the ring expansion of the thiazolidine ring of a penicillin. In this procedure, described in U.S. Pat. No. 3,275,626, the fused B-lactam ring of the penicillin molecule remains intact. This chemical conversion is carried out by heating a penicillin sulfoxide compound in the presence of an acidic reagent, such as acetic anhydride, to obtain predominantly a 7-acylamino-3-methyl-3-cephem-4-carboxylic acid ester (a desacetoxycephalosporin) and a 7-acylamino-3-methyl-3-acyloxycepham-4-carboxylic acid ester. Also produced in this chemical conversion is a 2-acyloxymethylpenicillin, otherwise designated as a 6-acylamino-2-methyl-2-acyloxymethylpenam-3-carboxylic acid ester.
U.S. Pat. No. 3,275,626 additionally discusses the possibility of converting a penicillin sulfoxide by heating it in the presence of any one of various acidic reagents. The ultimate relative proportions of the products resulting from such reactions depend to some extent upon the particular acid which is employed, with the substituents present in the acid, as well as the particular structure and relative strength of the acid having some effect on the product mix formed.
PRODUCED: CARRYING OUT THE REACTION OF A PENICILLIN SULFOXIDE ESTER WITH THIONYL CHLORIDE, IT HAS BEEN FOUND THAT THE FOLLOWING PRODUCTS ARE AMONG THOSE PRODUCED; ##SPC1##
And ##SPC2##
And ##SPC3##
It further has been found that a 2.alpha.-methyl-2.beta.-halomethyl penam (I) is unstable and gradually rearranges to the corresponding 3.beta.-halo-3.alpha.-methylcepham of the formula ##SPC4## [See, e.g., Netherlands Pat. No. 7,208,671.] This rearrangement occurs spontaneously at room temperature over a period of time ranging from several days to several months depending on the particular compound and the conditions to which it is subjected. The rearrangement can be greatly accelerated by subjecting the penam to an elevated temperature, for example, from about 50.degree.C. to about 100.degree.C., under which conditions, the rearrangement can be accomplished in as little as one hour. Conversion to the corresponding 3.alpha.-methyl-3.beta.-halocepham can also be effected by maintaining the unstable penam in a suitable inert solvent on a chromatographic column for a period of from about 24 to about 72 hours and then eluting the cepham product from the column.
Generally, the 2.beta.-bromomethyl penam compounds undergo such a rearrangement more rapidly than the corresponding 2.beta.-chloromethylpenam compounds.
It has been shown that a 6-imido-2-methyl-2-chloromethylpenam-3-carboxylic acid ester can be prepared from the corresponding 3-hydroxy-3-metylcepham such as designated by Formula III, by reacting said 3-hydroxy compound with thionyl chloride in the presence of triethylamine at elevated temperatures [S. Kukolja and S. R. Lammert, J. Amer. Chem. Soc., 94, 7169 (1972) ]. Attempts at preparing 6-acylamino-2-methyl-2-halomethylpenam-3-carboxylic acid esters from the related 3-hydroxy substituted cepham compounds under similar reaction conditions resulted in recovery of starting materials. Thus, the 6-acylamino-2-methyl-2-halomethylpenam-3-carboxylic acid esters have been inaccessible through previously described procedures which have been successfully applied to the preparation of the corresponding 6-imido-2-methyl-2-halomethylpenam compounds.
Briefly, in accordance with this invention, it has now been discovered that it is possible to convert a 7-acylamino-3-hydroxy-3-methylcepham-4-carboxylic acid ester having the structure depicted by Formula III (R=RCONH--) to a 6-acylamino-2.alpha.-methyl-2.beta.-halomethylpenam-3-carboxylic acid ester (I), an intermediate useful in the preparation of active desacetoxycephalosporin antibiotics.